Intravascular ultrasound-guided versus angiography-guided percutaneous coronary intervention for acute myocardial infarction with cardiogenic shock

The benefits of intravascular ultrasonography (IVUS)-guided percutaneous coronary intervention (PCI) in the clinical context of cardiogenic shock (CS) complicating acute myocardial infarction are lacking. We aimed to investigate the impact of IVUS-guided PCI in patients with AMI and CS. From the pooled data based on a series of Korean AMI registries during 2011–2020, we identified 1418 consecutive patients who underwent PCI with second generation drug-eluting stent (DES) for AMI and CS. The primary endpoint was the 1-year rate of target lesion failure (TLF), defined as the composite of cardiac death, target vessel myocardial infarction, and ischemic-driven target lesion revascularization. In total, 294 (20.7%) and 1124 (79.3%) underwent IVUS-guided and angiography-guided PCI with second generation DES implantation, respectively. The 1-year TLF was not significantly different between groups after IPTW analysis (hazard ratio 0.93, 95% confidence interval 0.65–1.34, p = 0.70). Additionally, the adjusted landmark analysis for TLF at 30 days and between 30 days and 1 year after PCI demonstrated no significant difference between the groups. In conclusion, in patients with AMI and CS who underwent PCI with second-generation DES, IVUS-guided PCI did not improve the 1-year TLF compared with angiography-guided PCI. Registration: URL: http://cris.nih.go.kr. KCT0000863 and KCT0008355.


Treatment
Patients diagnosed with AMI were treated according to contemporary guidelines 12,13 .The strategy for revascularization, techniques, vascular access, selection of devices, and adjunctive antithrombotic therapy including glycoprotein IIb/IIIa inhibitor were left to the discretion of each physician.All procedures were performed in accordance with standard interventional techniques.The decision to use IVUS was at the operator's discretion.Patients were recommended to receive optimal pharmacological therapy after PCI according to standard guidelines.For cardiogenic shock management, the use of intra-aortic balloon pump (IABP), extracorporeal membrane oxygenation (ECMO), and inotropic agents was also determined at the operator's discretion.

Endpoints
The primary endpoint was target lesion failure (TLF), defined as the composite of cardiac death, target vessel myocardial infarction (TV-MI), and ischemia-driven target lesion revascularization (ID-TLR) at 1 year after the index procedure.The secondary endpoints included all-cause mortality; individual components of TLF; definite/ probable stent thrombosis as defined by the Academic Research Consortium 14 ; and major adverse cardiovascular events (MACEs), including death from any cause, myocardial infarction (MI), and revascularization.Clinical outcomes at 30 days and between 30 days and 1 year were also compared.All-cause mortality was regarded as cardiac death unless a definite noncardiac cause was identified.TV-MI was defined as MI with evidence of myocardial necrosis in the vascular territory of a previously treated target vessel.Target lesion revascularization was considered ischemia-driven if any revascularization including PCI or bypass surgery for the target lesion was performed in ≥ 50% angiographic diameter stenosis with ischemic symptoms, positive results on a functional study, or ≥ 70% angiographic diameter stenosis with or without documented ischemia.

Statistical analysis
Data are presented as the mean ± standard deviation (SD) for continuous variables and frequency (percentage) for categorical variables.Between-group comparisons were performed using the independent two sample t-test for continuous variables and the chi-squared or Fisher's exact test for categorical variables as appropriate.The mean imputation for missing value of laboratory findings was performed to minimize the sample size loss.The cumulative incidence rate of clinical endpoints was estimated using the Kaplan-Meier method and compared between groups using the log-rank test.Cox proportional hazard regression analyses were performed to calculate hazard ratio (HR) with 95% confidence interval (CI) for each clinical endpoint associated with IVUS-or angiographyguided PCI.Landmark analysis was conducted at 30 days after PCI.Inverse probability of treatment weighting (IPTW) was used to adjust for confounding factors.The propensity score (PS) was estimated using multiple logistic regression analysis with all covariates.The standardized mean difference (SMD) was used to assess the balance of covariate distribution between the groups.Covariates with an SMD < 0.1 were considered balanced.The cumulative incidence rate of clinical endpoints was calculated using the IPTW-adjusted Kaplan-Meier estimators and compared between groups using IPTW-adjusted log-rank test.We also conducted sensitivity analyses using PS matching to enhance the validity of our results.The IVUS and angiography groups were matched in a 1:2 ratio without replacement using the nearest-neighbor method based on a PS with a 0.1-caliper width.Additionally, we performed univariable and multivariable logistic regression analyses to identify the determinants for IVUS use.Significant variables (i.e., P < 0.10) in the univariable analysis were included in the multivariable analysis.All statistical analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC, USA) and R software (version 4.1.1;R Foundation for Statistical Computing, Vienna, Austria).P < 0.05 was considered significant.

Baseline characteristics
The baseline characteristics are summarized in Tables 1 and 2 S1 and S2).
Regarding the secondary outcomes, risk of MACE, all-cause death, and cardiac death did not significantly differ between the two groups after adjustment, although the unadjusted analyses showed significantly lower rates in the IVUS-guided PCI group.There was no significant between-group difference in the risk of any MI, TV-MI, any revascularization, ID-TLR, and definite/probable stent thrombosis.The risk of TLF and MACE were comparable between the groups in both patients with STEMI and with NSTEMI (Supplementary Tables S3 and S4).No significant interaction was observed in the subgroup analyses (Supplementary Fig. S4).

Thirty-day outcome and landmark analysis
Supplementary Tables S5 and S6, and Fig. 3 present the clinical outcomes at 30 days and between 30 days and 1 year of follow-up in the IVUS-and angiography-guided PCI groups.Regarding short-term clinical outcomes, although the unadjusted rates for 30-day TLF and MACE were significantly lower in the IVUS-guided PCI group, multivariable, PS matching, and IPTW adjustment revealed that the risks of 30-day TLF and MACE, all-cause death, and cardiac death did not differ significantly between the two groups.TLF and MACE also did not differ before and after multiple sensitivity analyses.

Major factors influencing IVUS usage
In total, 7.2% (2095/28,949) patients were treated for CS complicating AMI between 2011 and 2020.Among them, 18.6% (354/1907) of patients underwent PCI with IVUS guidance, and the remaining 81.4% (1553) underwent PCI with angiography guidance.Among patients with AMI accompanied by CS, the rate of IVUS utilization has consistently remained over 10% (Fig. 4) in patients who underwent PCI.The primary factors for IVUS usage were younger patients (aged < 65 years), prior MI, left main disease, and multiple stent implantation (Table 4).
Although not significant, there was a trend towards higher IVUS utilization in patients with NSTEMI than in patients with STEMI.

Discussion
The main findings of the present study were as follows (Central Illustration).First, there was no difference in 1-year TLF risk between the IVUS-and angiography-guided PCI groups after adjustment for confounding factors.Second, the adjusted landmark analysis for TLF and MACE showed no significant differences between the two groups at within 30 days and between 30 days and 1 year.Third, the major factors for IVUS usage were younger patients, prior MI, left main disease, and multiple stent implantation.www.nature.com/scientificreports/IVUS-guided PCI is associated with better clinical outcomes than angiography-guided PCI in the secondgeneration DES era 15,16 .However, previous studies excluded patients with CS.Two AMI registries demonstrated that IVUS-guided PCI improved long-term clinical outcomes compared with angiography-guided PCI in realworld practice.However, one study using the KAMIR-NIH registry excluded patients with CS, whereas in another AMI registry, only approximately 8.7% (855/9846) of the patients had CS.Furthermore, no further subgroup analysis was conducted for patients with CS 8,9 .The role of intravascular imaging during revascularization is also not mentioned in the current guideline for the management of CS complicating MI 17 .Therefore, the importance of this study lies in its primary focus on comparing clinical outcomes between IVUS and angiography guidance in patients with CS derived from a dedicated AMI registry.
In this study, IVUS was consistently utilized in PCI procedures for 13-25% of all patients diagnosed with AMI and CS.The unusually high rate of IVUS penetration in the clinical context of AMI and CS might be attributed to several factors.First, the positive outcomes observed in randomized trials and dedicated AMI registries with IVUS guidance may have influenced the operators to choose PCI optimization even in patients with AMI and CS.Furthermore, the presence of left main disease was associated with IVUS utilization in the current study.Because Table 3. One-year outcome.Data are presented as the mean (SD), or n (%). a The confounding factors considered in the adjusted hazard ratio are age, sex, BMI, clinical presentation, hypertension, diabetes mellitus, dyslipidemia, current smoker, prior MI, prior revascularization, prior CVA, LVEF, eGFR, CK-MB, LDLcholeterol, CRP, DAPT, aspirin, P2Y12 inhibitor, ACEi or ARB, beta-blocker, statin, multi-vessel disease, culprit vessel, B2/C lesion, trans-radial approach, glycoprotein IIb/IIIa inhibitor, thrombus aspiration, thrombus type, successful PCI, multiple stent implatnation, stent length ≥ 60 mm, IABP, ECMO, in-hospital CPR and length of hospital stays.www.nature.com/scientificreports/current guidelines recommend IVUS guidance for left main-PCI, the operators may have faithfully adhered to this guideline in cases of CS complicating AMI 18 .Second, IVUS guidance was selected for patients with a history of MI and those undergoing multiple stent implantation, as they are considered as having high risk for subsequent ischemic events.Therefore, IVUS for these patients is aimed to minimize the risk of future ischemic events.Third, physicians seemed to favor IVUS-guided PCI among relatively young patients (age < 65 years), anticipating its long-term benefits in reducing the risk of ischemic event.Indeed, IVUS-guided PCI consistently reduced ischemic risks even beyond the 1-year follow up 19 .However, IVUS-guided PCI in patients with AMI and CS in the present study did not improve TLF reflecting ischemic events compared with angiography-guided PCI in the same population.In the landmark analysis, IVUS-guided PCI also did not reduce ischemic risk between 30 days and 1 year after the index procedure compared with angiography-guided PCI.Notably, the IVUS group showed an equal TLR rate to that of angiography alone despite the greater complexity of the PCI procedure.These results may offer valuable insights for physicians in prioritizing treatment strategies in the challenging scenario of CS complicating AMI.Nevertheless, the benefit of IVUS use in particular patients, such as those with distal lesions of the left main artery of with confusing angiographic findings, cannot be excluded.Given the substantial predictive value of CS in relation to stent thrombosis 20 , physicians have made efforts to optimize stent deployment under IVUS guidance, aiming to minimize acute or subacute ischemic events.However, adjusted landmark analysis from the present study showed no difference in 30-day clinical outcomes between the IVUS-and angiography-guided PCI groups.In the future, a well-designed, large scale randomized trial is needed to identify a specific patient subgroup in whom IVUS-guided PCI could enhance the clinical outcomes for individuals with AMI and CS.

Limitations
First, the non-randomized observational design introduced inherent selection and information biases.Using physician discretion to determine treatment strategy inevitably introduced the possibility of selection bias.Furthermore, the number of patients was largely different between the groups.Although, extensive sensitivity analyses were conducted to adjust for the measured or unmeasured confounding factors to minimize the bias from different baseline characteristics, the possibility of unmeasured confounders influencing the findings cannot be excluded.Second, despite the pooled analyses, differences between centers and operator's experiences on IVUS may affect the findings.Third, the decision to use IVUS was made at the operator's discretion.Fourth, detailed procedural data were missing.Additionally, we did not have the timing of intravascular imaging relative to the PCI procedure.Therefore, the use of IVUS-guided PCI did not guarantee the optimization of PCI, and the findings should be interpreted cautiously.Fifth, detailed procedural data procedure time, and total amount of contrast media were unavailable.Finally, procedure-related risks were not evaluated.
In conclusion, IVUS-guidance did not improve the 1-year TLF compared with angiography-guidance in patients with AMI and CS who underwent PCI with second-generation DES.Further, risk of TLF at 30 days and between 30 days and 1 year after PCI were also comparable between the two groups.The factors for IVUS usage were younger age, prior MI, LM coronary artery disease, and multiple stent implantation.

Figure 2 .
Figure 2. Kaplan-Meier of the rate of 1-year target lesion failure (TLF) and major adverse cardiac events (MACE) in IVUS-guided and angiography-guided PCI.TLF (A) and MACE (B).IPTW-adjusted log-rank p values are presented inside each panel.

Figure 3 .
Figure 3. Landmark analysis for target lesion failure (TLF) and major adverse cardiac events (MACE) before and after 30-days of follow-up.TLF (A) and MACE (B).IPTW-adjusted log-rank p values are presented inside each panel.

Figure 4 .
Figure 4. Intravascular ultrasound versus angiography-guided percutaneous coronary intervention in patients with acute myocardial infarction and cardiogenic shock.

Table 2 .
Lesion and procedural characteristics.Data are presented as the mean (SD), or n (%).

Table 4 .
Univariable and multivariable analyses on the determinants for IVUS usage.